Longitudinal assessment of cardiac structure and function in a novel transgenic mouse that over expresses the 1C- subunit of the L-type Ca2+ channel (alpha 1CTG) indicates that like droves of other boutique mice, this mouse, develops cardiac hypertrophy, during which adaptive Ca2+ regulatory mechanisms are mobilized. The remarkable orchestration among cardiomyocyte Ca2+ regulatory proteins in this model at 4months (mo) is instructive because it provides clues with respect to coordinated, adaptive remodeling of Ca2+ regulation to maintain a normal SR Ca2+ load at 4mo of age. Specifically, during the hypertrophic, pre-HF stage, while an L-type current of a larger amplitude triggers larger Ca2+ release from the SR to produce a whole cell Ca2+ transient of increased amplitude, neither the SR Ca2+ load, as assessed by caffeine induced Ca2+ release, nor diastolic cytosolic Ca2+ levels, nor Ca2+ spark characteristics, are altered. An overexpression of NCX protein, which enhances Ca2+ efflux to balance the enhanced Ca2+ influx via the overexpressed L-type Ca2+ channel prevents excess cytosolic calcium loading. However, between 8-11mo of age, the adapted, hypertrophic heart of the 1CTG mouse maladapts into a dilated, lethal cardiomyopathy. This mouse model, like some others, appears to recapitulate the Meerson concept of adaptation and maladaptation. But since HF is not manifested at the same time in all 8-11mo old mice, there is a window of opportunity in which myocyte properties in age-matched alpha 1CTG mice with advanced hypertrophy, but not failure (NFTG), can be compared to those from non-transgenic littermates (NTG), and to those from failing alpha1CTG (FTG) mice. Mice over-expressing the alpha1-subunit (pore) of the L-type Ca2+ channel (alpha1CTG) by 4months (mo) of age exhibit an enlarged heart, hypertrophied myocytes, increased Ca2+ current and Ca2+ transient amplitude, but a normal SR Ca2+ load.. With advancing age (811mo), some mice demonstrate advanced hypertrophy but are not in congestive heart failure (NFTG), while others evolve to frank dilated congestive heart failure (FTG). We demonstrate that older NFTG myocytes exhibit a hypercontractile state over a wide range of stimulation frequencies, but maintain a normal SR Ca2+ load compared to age matched non-transgenic (NTG) myocytes. However, at high stimulation rates (2-4Hz) signs of diastolic failure appear. The evolution of frank congestive failure is accompanied by a further increase in heart mass and myocyte size, and phospholamban and ryanadine receptor protein levels and phosphorylation are reduced. The SR Ca2+ load increases and Ca2+ release following excitation, increases further. An enhanced NCX function in FTG, as reflected by an accelerated relaxation of the caffeine-induced Ca2+ transient, is insufficient to maintain a normal diastolic Ca2+ during high rates of stimulation. Although a high SR Ca2+ release following excitation is maintained, the hypercontractile state is not maintained at high rates of stimulation, and signs of both systolic and diastolic contractile failure appear. Thus, the dilated cardiomyopathy that evolves in this mouse model exhibits signs of both systolic and diastolic failure, but not a deficient SR Ca2+ loading or release, as occurs in some other cardiomyopathic models. It is perplexing that the SR Ca2+ load increases during the evolution from NFTG to FTG, since ICa density does not increase, and Ca2+ efflux via NCX is augmented, it might be expected that mechanisms to reduce Ca2+ pumping into the SR might prevail: in many other HF models, SERCA2a becomes reduced, PLN increases, and its phosphorylation decreases. The increased SR Ca2+ load apparently results from an increased Ca2+ availability for SR pumping, as evidenced by an increase in diastolic Indo-1 fluorescence during pacing, which may also reflect an increase in the net cell Ca2+ load between the NFTG and FTG states. An increased RyR Ca2+ leak alterations in RyR1 might also contribute. Unlike some other heart failure models, RyR2 and RyR2-P decrease, in the FTG, another conundrum. Some reports suggest that PKA phosphorylation of RyR2 has little functional relevance for diastolic Ca2+ release if SR Ca2+ levels remain constant. Marks and coworkers in many studies and perspectives, indict RyR2 and Ca2+ leak as causal of arrhythmias and sensitivities to heart failure. The increased Ca2+ leak theory as well as the decreased SR Ca2+ content concept have not been confirmed by others. Our results, highly reproducible, demonstrate that frank heart failure can occur in the context of reduced protein and RyR2, phosphorylation at Serine 2809 and increased SR Ca2+ loading. This underscores the complexity of heart failure, and the caution that should be applied to any molecular conclusion at this point.